A Single-Arm, Phase II, Multicenter Clinical Study of Neoadjuvant Encorafenib Plus Cetuximab N01 and mFOLFOX6 in Patients With Locally Advanced BRAF V600E-Mutant Colorectal Cancer With or Without Resectable Metastases

Neoadjuvant Encorafenib, Cetuximab N01 and mFolfox6 for BRAF V600E Mutated/ pMMR Localized Colorectal Cancer With or Without Resectable Metastases: a Single Arm, Multi-center, Phase 2 Clinical Trial

This is a single-arm, multicenter, phase II clinical trial evaluating the safety and efficacy of neoadjuvant encorafenib plus cetuximab N01 and mFOLFOX6 in patients with locally advanced BRAF V600E-mutated colorectal cancer, with or without resectable metastases. Eligible patients will receive 8 weeks of neoadjuvant treatment with encorafenib, cetuximab N01, and mFOLFOX6, followed by tumor response assessment and radical surgery when appropriate. The primary endpoint is 18-month disease-free survival (DFS). Secondary endpoints include perioperative safety, objective response rate, pathological response rate, 1-year DFS, 3-year DFS, overall safety, and quality of life. This study aims to explore whether incorporating BRAF and EGFR targeted therapy into standard chemotherapy in the neoadjuvant setting can improve tumor control and long-term outcomes in this high-risk molecular subgroup of colorectal cancer.

Inclusion Criteria:

• The subjects voluntarily joined this study, signed an informed consent form, and showed good compliance;

• Age: 18-75 years old, PS score 0-1;

• Colorectal adenocarcinoma diagnosed by histopathology, preoperative staging: T4N0-2M0, T3N2M0, T0-4N0-2M1a (with metastatic lesions present, requiring MDT evaluation as resectable); PMMR/MSS, BRAF V600E mutation, and both NRAS and KRAS wild-type;

• Locally advanced colorectal cancer requires initial diagnosis of patients who have not received systematic treatment in the past. Patients with resectable metastatic lesions are required to have not received targeted therapy in the past, and new metastases after adjuvant therapy can be included in this study.

• The main organ functions well and meets the following criteria:

  1. Blood routine examination criteria (corrected for no blood transfusion or use of hematopoietic stimulating factor drugs within 7 days before screening): hemoglobin (HGB) ≥ 90g/L (if chronic anemia is caused by chronic blood loss from the tumor and the researcher evaluates the stability of vital signs, it can be included in the group); absolute neutrophil count (NEUT) ≥ 1.5 × 109/L; platelet count (PLT) ≥ 75 × 109/L;
  2. Biochemical tests must meet the following standards: total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN) (Gilbert syndrome subjects, ≤ 3 × ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ULN; serum creatinine (CR) ≤ 1.5ULN or creatinine clearance rate (CCR) ≥ 50ml/min;
  3. Coagulation or thyroid function tests must meet the following criteria: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (without anticoagulant therapy); thyroid stimulating hormone (TSH) ≤ ULN; If there are abnormalities, T3 and T4 levels should be examined (if there is no T3 in the center, T4 can be replaced by FT3 and FT4), and if the level is normal, it can be selected.

• Cardiac ultrasound evaluation: Left ventricular ejection fraction (LVEF) ≥ 50%.

Exclusion Criteria:

• Those who meet any of the following criteria will not be included in this trial:

• Patients with MSI-H/dMMR present;

• Patients with multiple metastases that cannot be resected;

• Combined diseases and medical history:

  1. Has had or is currently suffering from other malignant tumors within the past 3 years. The following situations can be included in the group:Cured cervical carcinoma in situ, non melanoma skin cancer, and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor infiltrating basement membrane)];
  2. Patients with active inflammatory bowel disease within the first 4 weeks of enrollment;
  3. Uncontrollable pleural effusion, pericardial effusion, or ascites that require repeated drainage;
  4. Unrelieved toxic reactions above CTCAE grade 1 caused by any previous anti-tumor treatment (excluding hair loss and ≤ grade 2 neurotoxicity caused by oxaliplatin);
  5. Within 4 weeks prior to the start of the study, any bleeding events ≥ CTCAE grade 3 occurred in patients with unhealed wounds, ulcers, or fractures;
  6. History of arterial/venous thrombotic events within 6 months, such as cerebrovascular accidents (including transient ischemic attacks, intracerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
  7. Individuals with a history of substance abuse involving psychotropic drugs who are unable to quit;
  8. Subjects with any severe and/or uncontrolled diseases, including: uncontrolled hypertension (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg despite standard antihypertensive treatment); myocardial ischemia or myocardial infarction ≥grade 2, arrhythmia (QTc ≥450 ms in males, QTc ≥470 ms in females, and ≥grade 2 congestive heart failure (New York Heart Association (NYHA) classification); active or uncontrolled severe infections (≥CTC AE grade 2 infection); cirrhosis, active hepatitis*; (*Active hepatitis [Hepatitis B reference: HBsAg positive and HBV DNA positive (>2500 copies/mL or >500 IU/mL); Hepatitis C reference: HCV antibody positive and HCV viral load exceeding the upper limit of normal] Note: For subjects meeting enrollment criteria, those with hepatitis B surface antigen positive or hepatitis B core antibody positive, or hepatitis C patients, must receive continuous antiviral treatment to prevent viral activation); renal failure requiring hemodialysis or peritoneal dialysis; history of immunodeficiency, including HIV positive or other acquired or congenital immunodeficiency diseases, or organ transplantation history; poorly controlled diabetes (fasting blood glucose (FBG) >10 mmol/L); urinalysis indicating proteinuria ≥++, and confirmed 24-hour urine protein quantification >1.0g; a history of confirmed neurological or psychiatric disorders requiring treatment, including epilepsy or dementia;

• Tumor-related symptoms and treatment: Previously received targeted drug therapy (including G12C inhibitors, bevacizumab, etc.);

• According to the investigator's judgment, subjects with serious diseases that pose a significant risk to their safety or affect the completion of the study, or those deemed ineligible for enrollment due to other reasons.